Method and apparatus for loading a beneficial agent into an expandable medical device

ABSTRACT

The present invention relates to method and apparatus for dispensing a beneficial agent into an expandable medical device. The method includes the step of placing an expandable medical device on a mandrel, the medical device forming a cylindrical device having a plurality of openings and dispensing a beneficial agent into the plurality of openings.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.10/447,587 filed May 28, 2003 which claims priority to U.S. ProvisionalPatent Application Ser. No. 60/412,489, filed on Sep. 20, 2002, each ofwhich are incorporated herein by reference in its entirety. Thisapplication is also a Continuation-in-Part of U.S. patent applicationSer. No. 09/948,989, filed on Sep. 7, 2001, which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The invention relates to a method and apparatus for loading a beneficialagent, such as a drug into an expandable medical device, and moreparticularly, the invention relates to a method and apparatus fordispensing a beneficial agent into an expandable medical device such asa stent.

DESCRIPTION OF THE RELATED ART

Implantable medical devices are often used for delivery of a beneficialagent, such as a drug, to an organ or tissue in the body at a controlleddelivery rate over an extended period of time. These devices may deliveragents to a wide variety of bodily systems to provide a wide variety oftreatments.

One of the many implantable medical devices which have been used forlocal delivery of beneficial agents is the coronary stent. Coronarystents are typically introduced percutaneously, and transportedtransluminally until positioned at a desired location. These devices arethen expanded either mechanically, such as by the expansion of a mandrelor balloon positioned inside the device, or expand themselves byreleasing stored energy upon actuation within the body. Once expandedwithin the lumen, these devices, called stents, become encapsulatedwithin the body tissue and remain a permanent implant.

Known stent designs include monofilament wire coil stents (U.S. Pat. No.4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337);and, most prominently, thin-walled metal cylinders with axial slotsformed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762;and 4,776,337). Known construction materials for use in stents includepolymers, organic fabrics and biocompatible metals, such as stainlesssteel, gold, silver, tantalum, titanium, and shape memory alloys, suchas Nitinol.

Of the many problems that may be addressed through stent-based localdelivery of beneficial agents, one of the most important is restenosis.Restenosis is a major complication that can arise following vascularinterventions such as angioplasty and the implantation of stents. Simplydefined, restenosis is a wound healing process that reduces the vessellumen diameter by extracellular matrix deposition, neointimalhyperplasia, and vascular smooth muscle cell proliferation, and whichmay ultimately result in renarrowing or even reocclusion of the lumen.Despite the introduction of improved surgical techniques, devices, andpharmaceutical agents, the overall restenosis rate is still reported inthe range of 25% to 50% within six to twelve months after an angioplastyprocedure. To treat this condition, additional revascularizationprocedures are frequently required, thereby increasing trauma and riskto the patient.

One of the techniques under development to address the problem ofrestenosis is the use of surface coatings of various beneficial agentson stents. U.S. Pat. No. 5,716,981, for example, discloses a stent thatis surface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). The patent offers detailed descriptions of methodsfor coating stent surfaces, such as spraying and dipping, as well as thedesired character of the coating itself: it should “coat the stentsmoothly and evenly” and “provide a uniform, predictable, prolongedrelease of the anti-angiogenic factor.” Surface coatings, however, canprovide little actual control over the release kinetics of beneficialagents. These coatings are necessarily very thin, typically 5 to 8microns deep. The surface area of the stent, by comparison is verylarge, so that the entire volume of the beneficial agent has a veryshort diffusion path to discharge into the surrounding tissue.

Increasing the thickness of the surface coating has the beneficialeffects of improving drug release kinetics including the ability tocontrol drug release and to allow increased drug loading. However, theincreased coating thickness results in increased overall thickness ofthe stent wall. This is undesirable for a number of reasons, includingincreased trauma to the vessel wall during implantation, reduced flowcross-section of the lumen after implantation, and increasedvulnerability of the coating to mechanical failure or damage duringexpansion and implantation. Coating thickness is one of several factorsthat affect the release kinetics of the beneficial agent, andlimitations on thickness thereby limit the range of release rates,duration of drug delivery, and the like that can be achieved.

In addition to sub-optimal release profiles, there are further problemswith surface coated stents. The fixed matrix polymer carriers frequentlyused in the device coatings typically retain approximately 30% of thebeneficial agent in the coating indefinitely. Since these beneficialagents are frequently highly cytotoxic, sub-acute and chronic problemssuch as chronic inflammation, late thrombosis, and late or incompletehealing of the vessel wall may occur. Additionally, the carrier polymersthemselves are often highly inflammatory to the tissue of the vesselwall. On the other hand, use of biodegradable polymer carriers on stentsurfaces can result in the creation of “virtual spaces” or voids betweenthe stent and tissue of the vessel wall after the polymer carrier hasdegraded, which permits differential motion between the stent andadjacent tissue. Resulting problems include micro-abrasion andinflammation, stent drift, and failure to re-endothelialize the vesselwall.

Another significant problem is that expansion of the stent may stressthe overlying polymeric coating causing the coating to plasticallydeform or even to rupture, which may therefore effect drug releasekinetics or have other untoward effects. Further, expansion of such acoated stent in an atherosclerotic blood vessel will placecircumferential shear forces on the polymeric coating, which may causethe coating to separate from the underlying stent surface. Suchseparation may again have untoward effects including embolization ofcoating fragments causing vascular obstruction.

In addition, it is not currently possible to deliver some drugs with asurface coating due to sensitivity of the drugs to water, othercompounds, or conditions in the body which degrade the drugs. Forexample, some drugs lose substantially all their activity when exposedto water for a period of time. When the desired treatment time issubstantially longer than the half life of the drug in water, the drugcannot be delivered by known coatings. Other drugs, such as protein orpeptide based therapeutic agents, lose activity when exposed to enzymes,pH changes, or other environmental conditions. These drugs which aresensitive to compounds or conditions in the body often cannot bedelivered using surface coatings.

Accordingly, it would be desirable to provide an apparatus and methodfor loading a beneficial agent into an expandable medical device, suchas a stent, for delivery of agents, such as drugs, to a patient.

SUMMARY OF THE INVENTION

The present invention relates to an apparatus and method for loading abeneficial agent in an expandable medical device.

In accordance with one aspect of the invention, a method for dispensinga beneficial agent into an expandable medical device includes the stepsof placing an expandable medical device on a mandrel, the medical deviceforming a cylindrical device having a plurality of openings; anddispensing a beneficial agent into at least a portion of the pluralityof openings.

In accordance with another aspect of the invention, a method for loadinga beneficial agent in an expandable medical device includes the steps ofdispensing a beneficial agent through a dispenser into a first openingin an expandable medical device; providing relative movement between thedispenser and the expandable medical device such that the dispenser ismoved from alignment with the first opening in the expandable medicaldevice to alignment with a second opening in the expandable medicaldevice; and dispensing the beneficial agent into the second opening inthe expandable medical device.

In accordance with a further aspect of the invention, an apparatus forloading a beneficial agent in an expandable medical device includes amandrel; an expandable medical device having a plurality of openings,the expandable medical device mounted on the mandrel; and a dispenserconfigured to dispense a beneficial agent into the plurality of openingsin the expandable medical device.

In accordance with a further aspect of the invention, a method forloading a stent with a beneficial agent includes the steps of providinga stent with a plurality of holes; and dispensing a beneficial agentthrough a piezo-electric micro-jet into the plurality of holes.

In accordance with an additional aspect of the invention, an apparatusfor loading a beneficial agent in a medical device comprises a dispenserconfigured to dispense a beneficial agent into the plurality of openingsin the medical device; an observation system configured to locate andidentify the plurality of openings; and a central processing unit forcontrolling the dispensing of the beneficial agent into the openings ofthe medical device, wherein an amount and location of droplets ofbeneficial agent dispensed into each of the openings in the medicaldevice is determined by the central processing unit based informationobtained from the observation system.

In accordance with another aspect of the invention, a system forcontrolling a delivery of a beneficial agent into a plurality ofopenings of a medical device includes an observation system for mappinga medical device to obtain an actual position of a plurality of openingsof the medical device; a central processing unit for comparing theactual position of the plurality of openings of the medical device to ananticipated position from a manufacturing specification; and a dispenserfor dispensing a fluid beneficial agent into the plurality of openings.

In accordance with a further aspect of the invention, a system forcontrolling a delivery of a beneficial agent into an opening includes amandrel having a plurality of expandable medical devices; a dispenserconfigured to dispense a first layer and a second layer of a beneficialagent into a plurality of openings in the expandable medical device; anda central processing unit for controlling the dispensing of thebeneficial agent into the openings of the expandable medical device.

In accordance with another aspect of the invention, a method of removingstents from a mandrel includes the steps of radially expanding thestents by injecting air into at least a portion of the mandrel toinflate the mandrel and expand the stents; deflating the mandrel; andsliding the expanded stents off the mandrel.

In accordance with another aspect of the invention a method of obtaininga quantity of a dry, solid form of an agent of interest comprises thesteps of providing a liquid which comprises an agent of interestdissolved or dispersed in a volatile liquid medium, depositing amicroquantity of the liquid onto a pre-selected site of a substrate, anddrying the microquantity by volatizing the volatile liquid medium toproduce a dry, solid form of the agent of interest.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a perspective view of a therapeutic agent delivery device inthe form of an expandable stent.

FIG. 2 is a cross-sectional view of a portion of a therapeutic agentdelivery device having a beneficial agent contained in an opening inlayers.

FIG. 3 is a cross-sectional view of a piezoelectric micro-jettingdispenser for delivery of a beneficial agent.

FIG. 4 is a cross-sectional view of a piezoelectric micro-jettingdispenser and an expandable medical device on a mandrel.

FIG. 5 is a perspective view of a system for loading an expandablemedical device with a beneficial agent.

FIG. 6 is a perspective view of a bearing for use with the system ofFIG. 5.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method and apparatus for loading abeneficial agent into an expandable medical device. More particularly,the invention relates to a method and apparatus for loading a beneficialagent in a stent.

First, the following terms, as used herein, shall have the followingmeanings:

The term “beneficial agent” as used herein is intended to have itsbroadest possible interpretation and is used to include any therapeuticagent or drug, as well as inactive agents such as barrier layers,carrier layers, therapeutic layers or protective layers.

The terms “drug” and “therapeutic agent” are used interchangeably torefer to any therapeutically active substance that is delivered to abodily conduit of a living being to produce a desired, usuallybeneficial, effect. The present invention is particularly well suitedfor the delivery of antineoplastic, angiogenic factors,immuno-suppressants, anti-inflammatories and antiproliferatives(anti-restenosis agents) such as paclitaxel and Rapamycin for example,and antithrombins such as heparin, for example.

The therapeutic agents used in the present invention include classicalsmall molecular weight therapeutic agents commonly referred to as drugsincluding all classes of action as exemplified by, but not limited to:antiproliferatives, antithrombins, antiplatelet, antilipid,anti-inflammatory, and anti-angiogenic, vitamins, ACE inhibitors,vasoactive substances, antimitotics, metello-proteinase inhibitors, NOdonors, estradiols, anti-sclerosing agents, alone or in combination.Beneficial agent also includes larger molecular weight substances withdrug like effects on target tissue sometimes called biologic agentsincluding but not limited to: peptides, lipids, protein drugs, enzymes,oligonucleotides, ribozymes, genetic material, prions, virus, bacteria,and eucaryotic cells such as endothelial cells, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. Otherbeneficial agents may include but not be limited to physical agents suchas microspheres, microbubbles, liposomes, radioactive isotopes, oragents activated by some other form of energy such as light orultrasonic energy, or by other circulating molecules that can besystemically administered.

The term “matrix” or “biocompatible matrix” are used interchangeably torefer to a medium or material that, upon implantation in a subject, doesnot elicit a detrimental response sufficient to result in the rejectionof the matrix. The matrix typically does not provide any therapeuticresponses itself, though the matrix may contain or surround atherapeutic agent, a therapeutic agent, an activating agent or adeactivating agent, as defined herein. A matrix is also a medium thatmay simply provide support, structural integrity or structural barriers.The matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic,lipophilic, amphiphilic, and the like.

The term “bioresorbable” refers to a matrix, as defined herein, that canbe broken down by either chemical or physical process, upon interactionwith a physiological environment. The bioresorbable matrix is brokeninto components that are metabolizable or excretable, over a period oftime from minutes to years, preferably less than one year, whilemaintaining any requisite structural integrity in that same time period.

The term “polymer” refers to molecules formed from the chemical union oftwo or more repeating units, called monomers. Accordingly, includedwithin the term “polymer” may be, for example, dimers, trimers andoligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000.

The term “openings” refers to holes of any shape and includes boththrough-openings and recesses.

Implantable Medical Devices with Holes

FIG. 1 illustrates a medical device 10 according to the presentinvention in the form of a stent design with large, non-deforming struts12 and links 14, which can contain openings (or holes) 20 withoutcompromising the mechanical properties of the struts or links, or thedevice as a whole. The non-deforming struts 12 and links 14 may beachieved by the use of ductile hinges which are described in detail inU.S. Pat. No. 6,241,762 which is incorporated hereby by reference in itsentirety. The holes 20 serve as large, protected reservoirs fordelivering various beneficial agents to the device implantation site.

As shown in FIG. 1, the openings 20 can be circular 22, rectangular 24,or D-shaped 26 in nature and form cylindrical, rectangular, or D-shapedholes extending through the width of the medical device 10. It can beappreciated that the openings 20 can be other shapes without departingfrom the present invention.

The volume of beneficial agent that can be delivered using openings 20is about 3 to 10 times greater than the volume of a 5 micron coatingcovering a stent with the same stent/vessel wall coverage ratio. Thismuch larger beneficial agent capacity provides several advantages. Thelarger capacity can be used to deliver multi-drug combinations, eachwith independent release profiles, for improved efficacy. Also, largercapacity can be used to provide larger quantities of less aggressivedrugs and to achieve clinical efficacy without the undesirableside-effects of more potent drugs, such as retarded healing of theendothelial layer.

FIG. 2 shows a cross-section of a medical device 10 in which one or morebeneficial agents have been loaded into the opening 20 in layers. Onemethod of creating such layers is to deliver a solution comprisingbeneficial agent, polymer carrier, and a solvent into the opening andevaporating the solvent to create a thin solid layer of beneficial agentin the carrier. Other methods of delivering the beneficial agent canalso be used to create layers.

According to another method for creating layers, a beneficial agent maybe loaded into the openings alone if the agent is structurally viablewithout the need for a carrier. The process can then be repeated untileach opening is partially or entirely filled. Examples of some methodsof creating such layers and arrangements of layers are described in U.S.patent application Ser. No. 09/948,989, filed on Sep. 7, 2001, which isincorporated herein by reference in its entirety. Although the layersare illustrated as discrete layers, the layers can also mix togetherupon delivery to result in an inlay of beneficial agent withconcentration gradients of therapeutic agents but without distinctboundaries between layers.

According to one example, the total depth of the opening 20 is about 100to about 140 microns, typically 125 microns and the typical layerthickness would be about 2 to about 50 microns, preferably about 12microns. Each typical layer is thus individually about twice as thick asthe typical coating applied to surface-coated stents. There would be atleast two and preferably about ten to twelve such layers in a typicalopening, with a total beneficial agent thickness about 25 to 28 timesgreater than a typical surface coating. According to one preferredembodiment of the present invention, each of the openings have an areaof at least 5×10⁻⁶ square inches, and preferably at least 7×10⁻⁶ squareinches. Typically, the openings are filled about 50% to about 75% fullof beneficial agent.

Since each layer is created independently, individual chemicalcompositions and pharmacokinetic properties can be imparted to eachlayer. Numerous useful arrangements of such layers can be formed, someof which will be described below. Each of the layers may include one ormore agents in the same or different proportions from layer to layer.The layers may be solid, porous, or filled with other drugs orexcipients. As mentioned above, although the layers are depositedseparately, they may mix forming an inlay without boundaries betweenlayers.

As shown in FIG. 2, the opening 20 is filled with a beneficial agent.The beneficial agent includes a barrier layer 40, a therapeutic layer30, and a cap layer 50.

Alternatively, different layers could be comprised of differenttherapeutic agents altogether, creating the ability to release differenttherapeutic agents at different points in time. The layers of beneficialagent provide the ability to tailor a delivery profile to differentapplications. This allows the medical device according to the presentinvention to be used for delivery of different beneficial agents to awide variety of locations in the body.

A protective layer in the form of a cap layer 50 is provided at a tissuecontacting surface of a medical device. The cap layer 50 can block orretard biodegradation of subsequent layers and/or blocks or retardsdiffusion of the beneficial agent in that direction for a period of timewhich allows the delivery of the medical device to a desired location inthe body. When the medical device 10 is a stent which is implanted in alumen, the barrier layer 40 is positioned on a side of the opening 20facing the inside of the lumen. The barrier layer 40 prevents thetherapeutic agent 30 from passing into the lumen and being carried awaywithout being delivered to the lumen tissue.

Typical formulations for therapeutic agents incorporated in thesemedical devices are well known to those skilled in the art.

Uses for Implantable Medical Devices

Although the present invention has been described with reference to amedical device in the form of a stent, the medical devices of thepresent invention can also be medical devices of other shapes useful forsite-specific and time-release delivery of drugs to the body and otherorgans and tissues. The drugs may be delivered to the vasculatureincluding the coronary and peripheral vessels for a variety oftherapies, and to other lumens in the body. The drugs may increase lumendiameter, create occlusions, or deliver the drug for other reasons.

Medical devices and stents, as described herein, are useful for theprevention of amelioration of restenosis, particularly afterpercutaneous transluminal coronary angioplasty and intraluminal stentplacement. In addition to the timed or sustained release ofanti-restenosis agents, other agents such as anti-inflammatory agentsmay be incorporated into the multi-layers incorporated in the pluralityof holes within the device. This allows for site-specific treatment orprevention any complications routinely associated with stent placementsthat are known to occur at very specific times after the placementoccurs.

Methods and Systems for Loading a Beneficial Agent in a Medical Device

FIG. 3 shows a piezoelectric micro-jetting dispenser 100 used todispense a beneficial agent into the opening of a medical device. Thedispenser 100 has a capillary tube 108 having a fluid outlet or orifice102, a fluid inlet 104, and an electrical cable 106. The piezoelectricdispenser 100 preferably includes a piezo crystal 110 within a housing112 for dispensing a fluid droplet through the orifice 102. The crystal110 surrounds a portion of the capillary tube 108 and receives anelectric charge that causes the crystal to vibrate. When the crystalvibrates inward, it forces a tiny amount of fluid out of the fluidoutlet 102 of the tube 108 to fill an opening 20 in a medical device. Inaddition, when the crystal vibrates outward, the crystal pullsadditional fluid into the tube 108 from a fluid reservoir connected tothe inlet 104 to replace the fluid that has been dispensed into theopening of the medical device.

In one embodiment as shown in FIG. 3, the micro-jetting dispenser 100includes an annular piezoelectric (PZT) actuator 110 bonded to a glasscapillary 108. The glass capillary 108 is connected at one end to afluid supply (not shown) and at the other end has an orifice 102generally in the range of about 0.5 to about 150 microns, and morepreferably about 30 to about 60 microns. When a voltage is applied tothe PZT actuator, the cross-section of the capillary glass 108 isreduced/increased producing pressure variations of the fluid enclosed inthe glass capillary 108. These pressure variations propagate in theglass capillary 108 toward the orifice 102. The sudden change incross-section (acoustic impedance) at the orifice 102, causes a dropletto be formed. This mode of producing droplets is generally called dropon demand (DOD).

In operation, the micro-jetting dispenser 100, depending on theviscosity and contact angle of the fluid, can require either positive ornegative pressure at the fluid inlet 104. Typically, there are two waysto provide pressure at the fluid inlet 104. First, the pressure at thefluid inlet 104 can be provided by either a positive or a negative headby positioning of the fluid supply reservoir. For example, if the fluidreservoir is mounted only a few millimeters above the dispenser 100, aconstant positive pressure will be provided. However, if the fluidreservoir is mounted a few millimeters below the dispenser 100, theorifice 102 will realize a negative pressure.

Alternatively, the pressure of the fluid at the inlet 104 can beregulated using existing compressed air or vacuum sources. For example,by inserting a pressure vacuum regulator between the fluid source andthe dispenser 100, the pressure can be adjusted to provide a constantpressure flow to the dispenser 100.

In addition, a wide range of fluids including beneficial agents can bedispensed through the dispenser 100. The fluids preferably have aviscosity of no greater than about 40 centipoise. The droplet volume ofthe dispenser 100 is a function of the fluid, orifice 102 diameter, andactuator driving parameter (voltage and timing) and usually ranges fromabout 50 picoliters to about 200 picoliters per droplet. If a continuousdroplet generation is desired, the fluid can be pressurized and asinusoidal signal applied to the actuator to provide a continuousjetting of fluids. Depending on the beneficial agent dispensed, eachdroplet may appear more like a filament.

It can be appreciated that other fluid dispensing devices can be usedwithout departing from the present invention. In one embodiment, thedispenser is a piezoelectric micro-jetting device manufactured byMicroFab Technologies, Inc., of Plano, Tex.

The electric cable 106 is preferably connected to associated driveelectronics (not shown) for providing a pulsed electric signal. Theelectric cable 106 provides the electric signal to control thedispensing of the fluid through the dispenser 100 by causing the crystalto vibrate.

FIG. 4 shows an expandable medical device in the form of a stent 140receiving a droplet 120 of a beneficial agent from a piezoelectricmicro-jetting dispenser 100. The stent 140 is preferably mounted to amandrel 160. The stent 140 can be designed with large, non-deformingstruts and links (as shown in FIG. 1), which contain a plurality ofopenings 142 without compromising the mechanical properties of thestruts or links, or the device as a whole. The openings 142 serve aslarge, protected reservoirs for delivering various beneficial agents tothe device implantation site. The openings 142 can be circular,rectangular, or D-shaped in nature and form cylindrical, rectangular orD-shaped holes extending through the width of the stent 140. Inaddition, openings 142 having a depth less than the thickness of thestent 140 may also be used. It can be appreciated that other shapedholes 142 can be used without departing from the present invention.

The volume of the hole 142 will vary depending on the shape and size ofthe hole 142. For example, a rectangular shaped opening 142 having awidth of 0.1520 mm (0.006 inches) and a height of 0.1270 mm (0.005inches) will have a volume of about 2.22 nanoliters. Meanwhile, a roundopening having a radius of 0.0699 mm (0.00275 inches) will have a volumeof about 1.87 nanoliters. A D-shaped opening having a width of 0.1520 mm(0.006 inches) along the straight portion of the D, has a volume ofabout 2.68 nanoliters. The openings according to one example are about0.1346 mm (0.0053 inches) in depth having a slight conical shape due tolaser cutting.

Although a tissue supporting device configuration has been illustratedin FIG. 1, which includes ductile hinges, it should be understood thatthe beneficial agent may be contained in openings in stents having avariety of designs including many of the known stents.

The mandrel 160 can include a wire member 162 encapsulated by an outerjacket 164 of a resilient or a rubber-like material. The wire member 162may be formed from a metallic thread or wire having a circularcross-section. The metallic thread or wire is preferably selected from agroup of metallic threads or wire, including Nitinol, stainless steel,tungsten, nickel, or other metals having similar characteristics andproperties.

In one example, the wire member 162 has an outer diameter of betweenabout 0.889 mm (0.035 inches) and about 0.991 mm (0.039 inches) for usewith a cylindrical or implantable tubular device having an outerdiameter of about 3 mm (0.118 inches) and an overall length of about 17mm (0.669 inches). It can be appreciated that the outer diameter of thewire member 162 will vary depending on the size and shape of theexpandable medical device 140.

Examples of rubber-like materials for the outer jacket 164 includesilicone, polymeric materials, such as polyethylene, polypropylene,polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyurethane,polyamides, polyethylene terephthalate (PET), and their mixtures andcopolymers. However, it can be appreciated that other materials for theouter jacket 164 can be implemented, including those rubber-likematerials known to those skilled in the art.

In one embodiment, the wire member 162 is encapsulated in a tubularouter jacket 164 having an inner diameter of about 0.635 mm (0.25inches). The outer jacket 164 can be mounted over the wire member 162 byinflating the tubular member to increase to a size greater than theouter diameter of the wire member 162. The tubular member can beinflated using an air pressure device known to those skilled in the art.The wire member 162 is placed inside of the outer jacket 164 by floatingthe outer jacket 164 of silicon over the wire member 162. However, itcan be appreciated that the wire member 162 can be encapsulated in anouter jacket of silicon or other rubber-like material by any methodknown to one skilled in the art.

In one embodiment for loading stents having a diameter of about 3 mm(0.118 inches) and a length of about 17 mm (0.669 inches), a wire member162 having an outer diameter of 0.939 mm (0.037 inches) is selected. Inone example, the wire member 162 is about 304.8 mm (12 inches) inlength. The outer jacket 164 has an inner diameter of about 0.635 mm(0.025 inches).

The expandable medical device or stent 140 is then loaded onto themandrel 160 in any method known to one skilled in the art. In oneembodiment, the stents 140 and the mandrel 160 are dipped into a volumeof lubricant to lubricate the stents 140 and the mandrel 160. The stents140 are then loaded onto the mandrel 160. The drying of the stents 140and the mandrel 160 create a substantially firm fit of the stents 140onto the mandrel 160. Alternatively, or in addition to drying, thestents 140 can be crimped onto the mandrel by a method known to oneskilled in the art onto the mandrel 160. The crimping ensures that thestents 140 will not move or rotate during mapping or filling of theopenings.

FIG. 5 shows a system 200 for loading a beneficial agent in anexpandable medical device. The system 200 includes a dispenser 210 fordispensing a beneficial agent into an opening of an expandable medicaldevice, a reservoir of beneficial agent 218 at least one observationsystem 220, and a mandrel 230 having a plurality of expandable medicaldevices 232 attached to the mandrel 230. The system 200 also includes aplurality of bearings 240 for supporting the rotating mandrel 230, ameans for rotating and translating the mandrel 250 along a cylindricalaxis of the expandable medical device 232, a monitor 260, and a centralprocessing unit (CPU) 270.

The dispenser 210 is preferably a piezoelectric dispenser for dispensinga beneficial agent into the opening in the medical device 232. Thedispenser 210 has a fluid outlet or orifice 212, a fluid inlet 214 andan electrical cable 216. The piezoelectric dispenser 200 dispenses afluid droplet through the orifice 212.

At least one observation system 220 is used to observe the formation ofthe droplets and the positioning of the dispenser 210 relative to theplurality of openings in the medical device 232. The observation system220 may include a charge coupled device (CCD) camera. In one embodiment,at least two CCD cameras are used for the filling process. The firstcamera can be located above the micro-jetting dispenser 210 and observesthe filling of the medical device 232. The first camera is also used formapping of the mandrel 230 as will be described below. A second camerais preferably located on a side of the micro-jetting dispenser 210 andobserves the micro-jetting dispenser 210 from a side or orthogonal view.The second camera is preferably used to visualize the micro-jettingdispenser during the positioning of the dispenser before loading of themedical device 232 with a beneficial agent. However, it can beappreciated that the observation system 220 can include any number ofvisualization systems including a camera, a microscope, a laser, machinevision system, or other known device to one skilled in the art. Forexample, refraction of a light beam can be used to count droplets fromthe dispenser. The total magnification to the monitor should be in therange of 50 to 100 times.

In one embodiment, a LED synchronized light 224 with the PZT pulseprovides lighting for the system 200. The delay between the PZT pulseand the LED pulse is adjustable, allowing the capture of the dropletformation at different stages of development. The observation system 220is also used in mapping of the mandrel 230 and medical devices 232 forloading of the openings. In one embodiment, rather than using a LEDsynchronized light 224, the lighting is performed using a diffusedfluorescent lighting system. It can be appreciated that other lightingsystems can be used without departing from the present invention.

A plurality of expandable medical devices 232 are mounted to the mandrel230 as described above. For example, a mandrel which is about 12 inchesin length can accommodate about 11 stents having a length of about 17 mmeach. Each mandrel 230 is labeled with a bar code 234 to ensure thateach mandrel is properly identified, mapped, and then filled to thedesired specifications.

The mandrel 230 is positioned on a plurality of bearings 240. As shownin FIG. 6, one example of the bearings 240 have a V-shaped notch 242.The mandrel 230 is positioned within the V-shaped notch 242 and securedusing a clip 244. The clip 244 is preferably a coil spring, however,other means of securing the mandrel within the V-shaped notch can beused including any type of clip or securing means can be used. Thebearings 240 can be constructed of a metallic material, preferablydifferent than the mandrel wire, such as stainless steel, copper, brass,or iron.

The mandrel 230 is connected to a means for rotating and translating themandrel 250 along the cylindrical axis of the medical device 232. Themeans for rotating and translating the mandrel 250 can be any type orcombination of motors or other systems known to one skilled in the art.

In one embodiment, the mandrel 250 and medical device 232 are moved froma first position to a second position to fill the openings of themedical device 232 with the beneficial agent. In an alternativeembodiment, the system further includes a means for moving thedispensing system along the cylindrical axis of the medical device 232from a first position to a second position.

A monitor 260 is preferably used to observe the loading of the medicaldevice 232 with a beneficial agent. It can be appreciated that any typeof monitor or other means of observing the mapping and loading processcan be used.

A central processing unit 270 (or CPU) controls the loading of themedical device 232 with the beneficial agent. The CPU 270 providesprocessing of information on the medical device 232 for the dispensingof the beneficial agent. The CPU 270 is initially programmed with themanufacturing specifications as to the size, shape and arrangement ofthe openings in the medical device 232. A keyboard 272 is preferablyused to assist with the loading of the CPU 270 and for input ofinformation relating to the loading process.

The medical devices 232 are preferably affixed to the mandrel 230 andmapped prior to the loading process. The mapping process allows theobservation system and associated control system to determine a preciselocation of each of the openings which may vary slightly from device todevice and mandrel to mandrel due to inaccuracies of loading the deviceson the mandrels. This precise location of each of the openings is thensaved as the specific map for that specific mandrel. The mapping of themandrel 230 is performed by using the observation system to ascertainthe size, shape and arrangement of the openings of each medical device232 located on the mandrel 230. Once the mandrel 230 including theplurality of medical devices 232 have been mapped, the mapping resultsare compared to the manufacturing specifications to provide adjustmentsfor the dispenser to correctly dispense the beneficial agent into eachof the holes of the medical device 232.

In an alternative embodiment, the mapping of the mandrel 230 isperformed on an opening by opening comparison. In operation, theobservation system maps a first opening in the medical device andcompares the mapping result to the manufacturing specifications. If thefirst opening is positioned as specified by the manufacturingspecifications, no adjustment is needed. However, if the first openingis not positioned as specified by the manufacturing specifications, anadjustment is recorded and an adjustment is made during the dispensingprocess to correct for the position which is different than as specifiedin the manufacturing specifications. The mapping is repeated for eachopening of the medical device until each medical device 232 has beenmapped. In addition, in one embodiment, if an opening is mapped and theopening is positioned pursuant to the manufacturing specifications, themapping process can be designed to proceed to map at every other openingor to skip any number of openings without departing from the presentinvention.

After the mandrel has been mapped, the medical device 232 is filled withthe beneficial agent based on the manufacturers' specification andadjustments from the mapping results. The CPU provides the programmeddata for filling of each medical device 232. The programmed dataincludes the medical device design code, date created, lot number beingcreated, number of medical devices 232 on the mandrel, volume of eachopening in the medical device 232, different beneficial agents to beloaded or dispensed into the openings in the medical device 232, thenumber of layers, drying/baking time for each layer, and any other data.

In one embodiment, the medical device 232 will have at least 10beneficial agent layers which will be filled including at least onebarrier layer, at least one therapeutic layer having a beneficial agent,and at least one cap layer. The beneficial agent layers may includelayers which vary in concentration and strength of each solution of drugor therapeutic agent, amount of polymer, and amount of solvent.

In operation, the operator will input or scan the bar code 234 of themandrel into the CPU 270 before the filling process begins. The initialfilling generally includes a mixture of polymer and solvent to create abarrier layer. Each of the openings are typically filled to about 80%capacity and then the mandrel is removed from the system and placed intoan oven for baking. The baking process evaporates the liquid portion orsolvent from the openings leaving a solid layer. The mandrel istypically baked for about 60 minutes plus or minus 5 minutes at about 55degrees C. To assist in error prevention, the CPU software receives thebar code of the mandrel and will not begin filling the second layeruntil at least 60 minutes since the last filling. The second layer andsubsequent layers are then filled in the same manner as the first layeruntil the opening has been filled to the desired capacity. The reservoir218 can also be bar coded to identify the solution in the reservoir.

The observation system 220 also can verify that the dispenser 210 isdispensing the beneficial agent into the openings through either humanobservation on the monitor 270 or via data received from the observationsystem and conveyed to the CPU to confirm the dispensing of thebeneficial agent in the openings of the medical device 232.Alternatively, refraction of a light beam can be used to count dropletsdispensed at a high speed.

The dispensers 100 run very consistently for hours at a time, but willdrift from day to day. Also, any small change in the waveform willchange the drop size. Therefore, the output of the dispenser 100 can becalibrated by firing a known quantity of drops into a cup and thenmeasuring the amount of drug in the cup. Alternatively, the dispenser100 can be fired into a cup of known volume and the number of dropsrequired to exactly fill it can be counted.

In filling the openings of the medical device 232, the micro-jettingdispenser 100 dispenses a plurality of droplets into the opening. In onepreferred embodiment, the dispenser is capable of dispensing 3000 shotsper second through a micro-jetting dispenser of about 40 microns.However, the droplets are preferably dispensed at between about 8 to 20shots per hole depending on the amount of fill required. Themicro-jetting dispenser fills each hole (or the holes desired) byproceeding along the horizontal axis of the medical device 232. The CPU270 turns the dispenser 100 on and off to fill the openingssubstantially without dispensing liquid between openings on the medicaldevice. Once the dispenser has reached an end of the medical device 232,the means for rotating the mandrel rotates the mandrel and a secondpassing of the medical device 232 along the horizontal axis isperformed. In one embodiment, the medical devices 232 are stents havinga diameter of about 3 mm and a length of about 17 mm and can be filledin about six passes. Once the medical device 232 is filled, thedispenser 210 moves to the next medical device 232 which is filled inthe same manner.

The CPU 270 insures that the mandrel is filled accurately by havingsafety factors built into the filling process. It has also been shownthat by filling the openings utilizing a micro-jetting dispenser, theamount of drugs or therapeutic agent used is substantially less thancoating the medical device 232 using previously known method includingspraying or dipping. In addition, the micro-jetting of a beneficialagent provides an improved work environment by exposing the worker to asubstantially smaller quantity of drugs than by other known methods.

The system 200 also includes an electrical power source 290 whichprovides electricity to the piezoelectric micro-jetting dispenser 210.

The medical devices 232 can be removed from the mandrel by expanding thedevices and sliding them off the mandrel. In one example, stents can beremoved from the mandrel by injecting a volume of air between the outerdiameter of the wire member 162 and the inner diameter of the outerjacket. The air pressure causes the medical device 232 to expand suchthat the inner diameter of the medical device 232 is greater than theouter diameter of the mandrel. In one embodiment, a die is place aroundthe mandrel to limit the expansion of the medical device 232 as the airpressure between the outer diameter of the wire member 162 and the innerdiameter of the outer jacket 164. The die can be constructed ofstainless steel or plastics such that the medical devices 232 are notdamaged during removal from the mandrel. In addition, in a preferredembodiment, the medical devices 232 are removed four at a time from themandrel. A 12-inch mandrel will accommodate about 11, 3 mm by 17 mmmedical devices having approximately 597 openings.

EXAMPLE 1

In the example below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   DMSO=Dimethyl Sulfoxide    -   IV=Inherent Viscosity    -   PLGA=poly(lactide-co-glycolide)

TABLE I Solutions Drug Polymer Solvent A None 4% PLGA DMSO 50/50 IV =0.82 DA 0.64% 8% PLGA DMSO paclitaxel 50/50 IV = 0.59 DD 0.14% 8% PLGADMSO paclitaxel 50/50 IV = 0.59 L None 8% PLGA DMSO 50/50 IV = 0.59

TABLE II Layer No., Layer No. Solution this Solution 1 A 1 2 A 2 3 A 3 4A 4 5 A 5 6 A 6 7 A 7 8 A 8 9 A 9 10 DA 1 11 DA 2 12 DD 1 13 L 1

A plurality of medical devices, preferably 11 medical devices permandrel are placed onto a series of mandrels. Each mandrel is bar codedwith a unique indicia which identifies at least the type of medicaldevice, the layers of beneficial agents to be loaded into the opening ofthe medical devices, and a specific identity for each mandrel. The barcode information and the mapping results are stored in the CPU forloading of the stent.

A first mixture of poly(lactide-co-glycolide) (PLGA) (BirminghamPolymers, Inc.), and a suitable solvent, such as DMSO is prepared. Themixture is loaded by droplets into holes in the stent. The stent is thenpreferably baked at a temperature of 55 degrees C. for about 60 minutesto evaporate the solvent to form a barrier layer. A second layer is laidover the first by the same method of filling polymer solution into theopening followed by solvent evaporation. The process is continued until9 individual layers have been loaded into the openings of the medicaldevice to form the barrier layer.

A second mixture of paclitaxel, PLGA, and a suitable solvent such asDMSO forming a therapeutic layer is then introduced into the openings ofthe medical device over the barrier layer. The solvent is evaporated toform a drug filled protective layer and the filling and evaporationprocedure repeated until the hole is filled until the desired amount ofpaclitaxel has been added to the openings of the medical device.

A third mixture of PLGA and DMSO is then introduced into the openingsover the therapeutic agent to form a cap layer. The solvent isevaporated and the filling and evaporation procedure repeated until thecap layer has been added to the medical device, in this embodiment, asingle cap layer has been added.

In order to provide a plurality of layers of beneficial agents having adesired solution, the reservoir is replaced and the piezoelectricmicro-jetting dispenser is cleaned. The replacement of the reservoir andcleaning of the dispenser insures that the different beneficial layershave a desired solution including the correct amount of drugs, solvent,and polymer.

Following implantation of the filled medical device in vivo, the PLGApolymer degrades via hydrolysis and the paclitaxel is released.

While the invention has been described in detail with reference to thepreferred embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made and equivalentsemployed, without departing from the present invention.

1. A method of obtaining a quantity of a dry, solid form of an agent ofinterest comprising: (a) providing a liquid which comprises an agent ofinterest dissolved or dispersed in a volatile liquid medium; (b)depositing a microquantity of the liquid onto a pre-selected site of asubstrate; and (c) drying the microquantity by volatizing the volatileliquid medium to produce a dry, solid form of the agent of interest;wherein the solution is delivered into the opening having a depth ofabout 125 to about 140 microns and an area of at least 5×10⁻⁶ squareinches.
 2. The method of claim 1, wherein step (b) comprises loading thebeneficial agent into the openings.
 3. The method of claim 1, whereinthe volatile liquid medium comprises a solvent for the agent of interestand the liquid of step (a) comprises a solution of the active agentdissolved in the solvent.
 4. The method of claim 1, wherein the agent ofinterest comprises a pharmaceutical agent.
 5. The method of claim 4,wherein the pharmaceutical agent comprises a peptide or a protein. 6.The method of claim 1, wherein the volatile liquid medium isnon-aqueous.
 7. The method of claim 1, wherein the microquantity has avolume between 1 nl and 1 μL.
 8. The method of claim 1, wherein themicroquantity has a volume between 10 nl and 500 nl.
 9. The method ofclaim 8, wherein the microscale reservoir has a volume between 1 nl and100 μL.
 10. The method of claim 1, wherein step (b) comprises depositingtwo or more discrete microquantities onto two or more discretepreselected sites, respectively.
 11. The method of claim 10, wherein thediscrete preselected sites are provided on a single substrate.
 12. Themethod of claim 10, wherein the single substrate comprises 100 or morediscrete preselected sites.
 13. The method of claim 10, wherein each ofthe two or more preselected sites is a microscale reservoir.